Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication ZYNLONTA is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1) ] . FDA label
Also known as ZYNLONTA, ADCT-402, ADC ADCT-402, Anti-CD19 PBD-conjugate ADCT-402, Loncastuximab Tesirine-lpyl
Loncastuximab tesirine · 13 trials · 26 indications
Evaluated per 2014 Lugano criteria. An exact 95% confidence interval will be calculated.
CR rate is defined as the Complete Response (CR)/n, where n is the number of participants. The proportion of patients with best overall response of complete response (CR), per Cheson criteria if disease is not PET (Positron emission tomography)-avid in initial screening and by revised Lugano criteria if screening PET-CT demonstrated PET-avid disease.CR will be defined by a Deauville score of ≤ 3.
CR rate is defined as the Complete Response (CR)/n, where n is the number of participants. The proportion of patients with best overall response of complete response (CR), per Cheson criteria if disease is not PET-avid in initial screening and by revised Lugano criteria if screening PET-CT demonstrated PET-avid disease.CR will be defined by a Deauville score of ≤ 3.
Occurrence of an objective response (OR) i.e. Complete Response (CR) or Partial Response (PR) after 12 weeks of treatment assessed by Independent Central Review (according to International Paediatric Non-Hodgkin Lymphoma Response Criteria)
Occurrence of CR within a maximum of three cycles of treatment assessed by Independent Central Review (according to International Paediatric Non-Hodgkin Lymphoma Response Criteria)
Overall Response Rate= Minor response (\>25%-50% reduction in serum IgM from baseline) + Partial Response (\>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (\>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
To evaluate the efficacy of SOC CAR T-cell therapy in patients with R/R large B-cell lymphoma following bridging with lonca-R.
To evaluate toxicities post CAR-T
To evaluate toxicities post CAR-T
To evaluate toxicities post CAR-T
Complete Response rate will be reported as the number of participants achieving complete response (CR) to study therapy. Response to therapy will be assessed using Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET) (FDG-PET)/ Computerized Tomography (CT) following Lugano 2014 criteria by week 12 of treatment.
ORR, as determined by central review according to the 2014 Lugano classification, defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR).
Maximum Tolerated Dose (MTD): MTD is defined as the highest dose under consideration that has an estimated DLT probability below 25% based upon the Bayesian optimal interval design. The MTD will be decided based on the BOIN decision rules set for phase 1a portion of the study.
To assess the Recommended Phase 2 Dose (RP2D) of loncastuximab tesirine and rituximab in participants with post-transplant lymphoproliferative disorders (PTLD).
To assess the efficacy of the combination of lonca-R based on CR rate after 4 cycles.
Recommended phase 2 dose of loncastuximab tesirine in combination with acalabrutinib
Frequency and severity of TEAEs and treatment-emergent serious adverse events (TESAEs). TEAEs and TESAEs will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
ECOG performance status will be measured on a scale from grades 0-5, where a higher grade indicates a worse outcome.
A DLT is defined as any of the following events, except those that are clearly due to underlying disease or extraneous causes: A hematologic DLT is defined as: * CTCAE Grade 3 or 4 febrile neutropenia or neutropenic infection. * CTCAE Grade 4 neutropenia lasting \>7 days. * CTCAE Grade 4 thrombocytopenia. * CTCAE Grade 3 thrombocytopenia with clinically significant bleeding, or Grade 3 thrombocytopenia requiring a platelet transfusion. * CTCAE Grade 4 anemia. A non-hematologic DLT is defined as: * CTCAE Grade 4 tumor lysis syndrome (TLS). Grade 3 TLS will not constitute DLT unless it leads to irreversible end-organ damage. * CTCAE Grade 3 or higher AE (including nausea, vomiting, diarrhea, and electrolyte imbalances lasting more than 48 hours despite optimal therapy; excluding all grades of alopecia). * CTCAE Grade 3 or higher hypersensitivity reaction (regardless of premedication). * CTCAE Grade 2 or higher skin ulceration.
The recommended dose was established by the dose escalation steering committee and based on safety findings during Part 1 of the study.
An adverse event (AE) is defined as any untoward medical occurrence in a participants enrolled into this study regardless of its causal relationship to study drug. A TEAE is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug.
An adverse event (AE) is defined as any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study drug. A treatment emergent AE (TEAE) is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug. An SAE is defined as any event that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
| Arm | Type | Description |
|---|---|---|
| Part 1: Loncastuximab Tesirine + Rituximab (Lonca-R) | EXPERIMENTAL | Part 1 consists of a non-randomized safety run-in period evaluating the study drug for the first 20 participants. Participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m\^2 Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m\^2 Q3W for up to 6 additional cycles. |
| Part 2: Loncastuximab Tesirine + Rituximab (Lonca-R) | EXPERIMENTAL | Randomized participants will receive Lonca-R on Day 1 of each cycle for up to 8 cycles, where 1 cycle is 3 weeks. Lonca-R will be administered via an intravenous infusion of loncastuximab tesirine 150 µg/kg + rituximab 375 mg/m\^2 every Q3W for 2 cycles, then loncastuximab tesirine 75 µg/kg + rituximab 375 mg/m\^2 Q3W for up to 6 additional cycles. |
| Part 2: Standard Immunochemotherapy (R-GemOx) | ACTIVE_COMPARATOR | Randomized participants will receive R-GemOx consisting of rituximab, gemcitabine and oxaliplatin as a standard immunochemotherapy treatment on Day 1 or Day 2 of each cycle for up to 8 cycles, where 1 Cycle is 2 weeks. R-GemOx will be administered via an intravenous infusion of rituximab 375 mg/m\^2 + gemcitabine 1000 mg/m\^2 + oxaliplatin 100 mg/m\^2 every 2 weeks (Q2W) for up to 8 cycles. |
| Treatment (Lonca-R, DA-EPOCH-R) | EXPERIMENTAL | Patients receive rituximab IV, loncastuximab tesirine IV, etoposide IV, doxorubicin IV, vincristine IV, prednisone PO, and cyclophosphamide IV on study. Patients also undergo collection of blood samples and bone marrow aspiration and biopsy at screening and CT or PET/CT at screening, throughout the study, and during follow up. |
| Loncastuximab tesirine Cycles 1-6 | EXPERIMENTAL | Patients will be treated with loncastuximab tesirine for a total of 6 cycles on Day 1 (+/-3) of each 21 day (3 week) cycle. The total duration of treatment is approximately 18 weeks (4.5 months) |
| Treatment Arm I - BsAb - Odronextamab | EXPERIMENTAL | Patients will receive odronextamab given as an intravenous infusion weekly for 12 weeks, then every two weeks until nine months, and every four weeks thereafter until progression or for a maximum of two years |
| Treatment Arm II - ADC with Standard Chemotherapy - Loncastuximab tesirine with modified R-ICE | EXPERIMENTAL | Patients will receive loncastuximab tesirine given as a 30-minute intravenous infusion with each cycle of modified R-ICE (maximum three cycles) |
| Treatment Arm III - CAR T-cells - TBC | EXPERIMENTAL | Patients will receive CAR-T cell therapy - agent TBC |
| Loncastuximab Tesirine + Dexamethasone | EXPERIMENTAL | Participants will be given * Loncastuximab Tesirine on Day 1 of every 28 day study cycle and continue for up to 6 cycles. Participants will also receive pre-medications to reduce the chance of having a sensitivity reaction to the study treatment. Participants who tolerate the study treatment without a reaction may have pre-medications changed per determination of their doctor. * Dexamethasone will be given prior to study treatment on Day -1 or up to 2 hours prior to loncastuximab tesirine and the day after treatment |
| Treatment: All Patients | EXPERIMENTAL | The study will investigate the effectiveness of Loncastuximab tesirine and Rituximab (Lonca-R) prior to standard of care CAR-T cell therapy. |
| Loncastuximab tesirine + Rituximab | EXPERIMENTAL | During the 12-week Induction Phase (Cycles 1 to 4), participants will receive loncastuximab tesirine on days 1 of each 3-week cycle for Cycles 1 through 4; and rituximab on days 1, 8, 15 of Cycle 1 and day 1 of Cycle 2. Maintenance Phase 1 (Cycle 5) is 8 weeks: Participants achieving complete response (CR) or partial response (PR) during the Induction Phase will receive loncastuximab tesirine once every 3-weeks; and rituximab once during week 7 or 8. Participants achieving a response of Stable Disease (SD) or Progressive Disease (PD) will be taken off treatment. Maintenance Phase 2 (Cycles 6 and 7) is 16 weeks: * Participants achieving CR during Maintenance Phase 1 receive rituximab once during week 7 or 8 of Cycles 6 and 7. * Participants achieving PR during Maintenance Phase 1 receive loncastuximab tesirine once every 3-weeks over each 8 week cycle; and rituximab once during week 7 or 8 of Cycles 6 and 7. * Participants achieving SD or PD will be taken off treatment. |
| Loncastuximab tesirine | EXPERIMENTAL | Participants will receive loncastuximab tesirine as an IV infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg Q3W for 2 cycles, then 75 μg/kg Q3W for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. |
| Dose Level 1 (starting dose): SD or PD | EXPERIMENTAL | Dose Level 1: * Loncastuximab tesirine: 0.075 mg/kg IV every 3 weeks * Rituximab: 375 mg/m2 IV This arm included participants who had SD (Stable Disease) or PD (Progressive Disease) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they do not achieve a response, they will come off the study but will be monitored for survival. |
| Dose Level 1 (starting dose): PR | EXPERIMENTAL | Dose Level 1: * Loncastuximab tesirine: 0.075 mg/kg IV every 3 weeks * Rituximab: 375 mg/m2 IV This arm included participants who had a Partial Response (PR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve PR, they will have the option to receive either rituximab consolidation or R-CHOP (at the physician's discretion). |
| Dose Level 1 (starting dose): CR | EXPERIMENTAL | Dose Level 1: * Loncastuximab tesirine: 0.075 mg/kg IV every 3 weeks * Rituximab: 375 mg/m2 IV This arm included participants who had a Complete Response (CR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve a CR after 4 cycles of Lonca-R, they will receive rituximab consolidation (SOC). |
| Dose Level 2: SD or PD | EXPERIMENTAL | Dose Level 2: * Loncastuximab tesirine: 0.15 mg/kg IV every 3 weeks for the first 2 cycles, then 0.075 mg/kg starting C3 * Rituximab: 375 mg/m2 IV This arm included participants who had SD (Stable Disease) or PD (Progressive Disease) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they do not achieve a response, they will come off the study but will be monitored for survival. |
| Dose Level 2: PR | EXPERIMENTAL | Dose Level 2: * Loncastuximab tesirine: 0.15 mg/kg IV every 3 weeks for the first 2 cycles, then 0.075 mg/kg starting C3 * Rituximab: 375 mg/m2 IV This arm included participants who had a Partial Response (PR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve PR, they will have the option to receive either rituximab consolidation or R-CHOP (at the physician's discretion). |
| Dose Level 2: CR | EXPERIMENTAL | Dose Level 2: * Loncastuximab tesirine: 0.15 mg/kg IV every 3 weeks for the first 2 cycles, then 0.075 mg/kg starting C3 * Rituximab: 375 mg/m2 IV This arm included participants who had a Complete Response (CR) after the first 6 weeks of treatment. Lonca-R will be administered for 4 cycles with response assessment at 6 weeks (+/- 1 week) following the last Lonca-R treatment. If they achieve a CR after 4 cycles of Lonca-R, they will receive rituximab consolidation (SOC). |
| Dose Level 1: | EXPERIMENTAL | 45 µg/kg Loncastuximab Tesirine every 21 days + Acalabrutinib 100 mg BID for 12 cycles |
| Dose Level 2 | EXPERIMENTAL | 60 µg/kg Loncastuximab Tesirine every 21 days + Acalabrutinib 100 mg BID for 12 cycles |
| Dose Level 3 | EXPERIMENTAL | 75 µg/kg Loncastuximab Tesirine every 21 days + Acalabrutinib 100 mg BID for 12 cycles |
| Dose level 4: | EXPERIMENTAL | 90 µg /kg Loncastuximab Tesirine (for first 2 cycles followed by 75µg/kg for subsequent 10 cycles) + Acalabrutinib 100 mg BID for a total of 12 cycles. |
| Part 1 (Dose Escalation): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C) | EXPERIMENTAL | Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive polatuzumab vedotin at a dose of 1.8 mg/kg on D1 of each cycle, infusion will be started one hour after end of loncastuximab tesirine infusion. |
| Part 1 (Dose Escalation): Loncastuximab Tesirine + Glofitamab (Arm E) | EXPERIMENTAL | Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on D2 of Cycle (C) 1 and then D1 of all other cycles (where each cycle is 21 days). Participants will also receive glofitamab 2.5 mg on C1 D8, 10 mg on C1 D15 and 30 mg for cycles 2-12 D1. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1. |
| Part 1 (Dose Escalation): Loncastuximab Tesirine + Mosunetuzumab (Arm F) | EXPERIMENTAL | Participants will receive escalating doses (90 µg/kg to 150 µg/kg) of loncastuximab tesirine on Day (D) 1 of each cycle (where each cycle is 21 days). Participants will also receive mosunetuzumab 5 mg on C1 D1, 45 mg for C1 D8, C1 D15 and cycles 2-8 D1. |
| Part 2 (Dose Expansion): Loncastuximab Tesirine + Polatuzumab Vedotin (Arm C) | EXPERIMENTAL | Participants with B-NHL will receive loncastuximab tesirine in combination with polatuzumab vedotin at the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) if favorable results of Part 1 are received. |
| Part 2 (Dose Expansion): Loncastuximab Tesirine + Glofitamab (Arm E) | EXPERIMENTAL | Participants with B-NHL will receive loncastuximab tesirine in combination with glofitamab at the MTD and/or RDE if favorable results of Part 1 are received. In addition participants will receive obinutuzumab pre-treatment 1000 mg on C1 D1. |
| Part 2 (Dose Expansion): Loncastuximab Tesirine + Mosunetuzumab (Arm F) | EXPERIMENTAL | Participants with B-NHL will receive loncastuximab tesirine in combination with mosunetuzumab at the MTD and/or RDE if favorable results of Part 1 are received. |
| Part 1: ADCT-402 dose escalation | EXPERIMENTAL | In Part 1 (dose escalation) participants will receive intravenous (IV) infusions of ADCT-402 at escalating doses, according to a 3+3 study design. Doses will be escalated from 15 µg/kg to 200 µg/kg on Day 1 of each cycle, with cycle lengths of 3 or 6 weeks. |
| Part 2: ADCT-402 dose expansion | EXPERIMENTAL | In Part 2 (expansion), participants will be assigned to the recommended dose level(s) and schedule(s) of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee. Participants will receive intravenous (IV) infusions of ADCT-402 at either 120 μg/kg or 150 μg/kg on Day 1 of each 3 week cycle (Q3W). |
| Name | Type | Description |
|---|---|---|
| Loncastuximab Tesirine | DRUG | Intravenous Infusion |
| Rituximab | DRUG | Intravenous Infusion |
| Gemcitabine | DRUG | Intravenous Infusion |
| Oxaliplatin | DRUG | Intravenous Infusion |
| Cyclophosphamide | DRUG | Given IV |
| Doxorubicin | DRUG | Given IV |
| Etoposide | DRUG | Given IV |
| Prednisone | DRUG | Given PO |
| Vincristine | DRUG | Given IV |
| Loncastuximab tesirine 150 µg/Kg | DRUG | Participants will be treated with loncastuximab tesirine at a dose of 150 µg/Kg given as an intravenous infusion (given as per treatment guidelines for 30 minutes or longer) on Day 1 (+/- 3 days) of each 21 day cycle for Cycle 1 - 2. |
| Loncastuximab tesirine 75µg/Kg | DRUG | Participants will be treated with loncastuximab tesirine at a dose of 75 µg/Kg given as an intravenous infusion (given as per treatment guidelines for 30 minutes or longer) on Day 1 (+/- 3 days) of each 21 day cycle for Cycle 3 - 6. |
| Odronextamab | DRUG | CD20xCD3 bispecific antibody |
| Ifosfamide | DRUG | Modified R-ICE chemotherapy |
| Carboplatin | DRUG | Modified R-ICE chemotherapy |
| Etoposide Phosphate | DRUG | Modified R-ICE (Treatment Arm II) |
| Dexamethasone | DRUG | Modified R-ICE chemotherapy |
| CAR T-cells (TBC) | BIOLOGICAL | Modified R-ICE chemotherapy |
| Loncastuximab tesirine and rituximab (Lonca-R) | DRUG | Patients will receive stereotactic radiosurgery (SRS) followed by a brain MRI approx. 3 weeks after SRS. This will be followed by loncastuximab tesirine and rituximab administered intravenously for a total of 6 cycles (every 21 days). |
| Rituximab or rituximab biosimilar | DRUG | Rituximab or rituximab biosimilar will be administered by IV at 375 mg/m2 on Day 1 of every cycle. Lonca will be administered first, followed by rituximab (with a 30 min wait time between the two agents) |
| Loncastuximab Tesirine and Acalabrutinib | DRUG | Will be given on Day 1 of each cycle with each cycle being 21 days, and is being added to BID Acalabrutinib |
| Polatuzumab Vedotin | DRUG | IV infusion |
| Glofitamab | DRUG | IV infusion |
| Mosunetuzumab | DRUG | Subcutaneous (SC) injection |
| Obinutuzumab | DRUG | IV infusion |
| ADCT-402 | DRUG | intravenous infusion |
Inclusion Criteria: * Male or female participant aged 18 years or older * Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization classification (including participants with DLBCL transformed from indolent lymphoma), or high-grade B-cell lymphoma, with MYC and BCL2 and/or BC...
Loncastuximab tesirine is being studied in B-cell non-Hodgkin lymphoma, central nervous system lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma refractory, double-expressor lymphoma, and follicular lymphoma. It is also being evaluated in post-transplant lymphoproliferative disorder and as bridging therapy before CAR-T in large B-cell lymphoma.
Loncastuximab tesirine targets CD19, a protein found on the surface of B cells. It is an antibody-drug conjugate, meaning the CD19-targeting antibody delivers a cytotoxic payload to CD19-expressing cells. This mechanism is being explored across several B-cell malignancies.
Loncastuximab tesirine is being developed by ADC Therapeutics SA, which trades under the ticker ADCT. The company is sponsoring clinical trials of the agent in multiple B-cell lymphoma indications.
Loncastuximab tesirine is in Phase 1 development according to the overall program status. Individual trials span Phase 1 and Phase 2, including a Phase 1 trial in post-transplant lymphoproliferative disorder and a Phase 2 trial in large B-cell lymphoma. It is investigational and not approved.
Loncastuximab tesirine is being studied in several trials, including NCT07573436 (PLUTO) in post-transplant lymphoproliferative disorder, NCT06788964 (CORAL) as bridging therapy before CAR-T in large B-cell lymphoma, NCT06607549 (SOLAR) in central nervous system lymphoma, and NCT05991388 in pediatric and adolescent relapsed/refractory B-cell non-Hodgkin lymphoma.